Proliferative vitreoretinopathy (PVR) occurs in approximately 5-10% of the patients that undergo retinal re-attachment surgery. There is no effective non-surgical therapy for PVR, and it is a disease priority of the NEI. Not knowing the molecular mediators of PVR constitutes a major roadblock in developing effective therapies for PVR. Work from many labs indicates that growth factors and their receptors appear to be among the molecular mediators of PVR. Our working hypothesis is that upon entry into the vitreous, cells encounter growth factors that induce cellular events intrinsic to PVR. Identifying the vitreal growth factors that promote PVR and determining their mechanism of action will unveil a cornucopia of therapeutic target for PVR. In the last grant period we made two major discoveries. First, although platelet-derived growth factors (PDGFs) were among the growth factors present in the vitreous of patients and animals experiencing PVR, they were not the only growth factors that activated PDGFR and promoted PVR. Growth factors outside of the PDGF family (non-PDGFs) indirectly activated PDGFR1 by a reactive oxygen species (ROS)-dependent mechanism that we are calling transactivation. Second, we discovered that PDGF-C was the predominant PDGF isoform in the vitreous of patients and experimental animals experiencing PVR, and that plasmin was the major protease that processed it to the CUB and core domains. Furthermore, the CUB domain was required for experimental PVR, and it induced contraction of cells embedded in collagen gels. The immediate goals of this grant are to further test the idea that the CUB domain of PDGF-C is promoting experimental PVR, and to fully elucidate the underlying mechanism (aim 1); to assess the contribution of transactivation of the PDGFR in experimental PVR (aim 2); and test if neutralizing vitreal agents that promote PVR-related events is a suitable strategy to prevent experimental PVR (aim 3). Our findings will substantially advance our current appreciation of how growth factors promote PVR and establish the foundation necessary to develop pharmacological (non-surgical) approaches to prevent and manage PVR. PUBLIC HEALTH RELEVANCE: Proliferative vitreoretinopathy (PVR) is the major cause for failure of retinal reattachment surgery for rhegmatogenous retinal detachment. While its occurrence is relatively low (approximately 5-10%) PVR remains a difficult disease to treat. With the exception of surgical intervention, for which 20-40% of the patients fail to achieve anatomical success, there is no treatment for individuals afflicted with PVR, and hence there is an acute need to develop non-surgical-based therapies for patients with PVR.